Many narcotic actions of morphine and other opioid ligands are mediated via μ opioid receptors, and these effects are reversed by antagonists (naloxone, naltrexone) thought to compete for the same receptor. We present evidence from β-funaltrexamine (β-FNA) protection studies in guinea pig ileal longitudinal muscle (GPI) suggesting antagonists act via a separate recognition site coupled to the μ receptor. We evaluated the ability of opioid agonists and antagonists to protect against β-FNA-induced irreversible antagonism of morphine's effects. Results showed that antagonists (nalorphine, naloxone, naltrexone, diprenorphine) afforded better protection than agonists (morphine, β-FOA, DAME, etorphine, ethylketazocine). The protective ability correlated with antagonist potency (rank order: nalorphine < naloxone < naltrexone < diprenorphine), matching their K_e values, rather than agonist activity. These findings support the presence of separate recognition sites mediating opioid agonism and antagonism. A model is proposed where a μ receptor subunit is associated with a regulatory subunit containing a p site (topographically similar but non-identical to the μ receptor): agonists have higher affinity for the μ receptor, while antagonists favor the p site; occupation of the p site induces a vectorial decrease in the affinity of the μ receptor.